Targeting the altered redox status of
cancer cells is emerging as an interesting approach to potentiate
chemotherapy. However, to maximize the effectiveness of this strategy and define the correct chemotherapeutic associations, it is important to understand the
biological consequences of chronically exposing
cancer cells to
reactive oxygen species (ROS). Using an H(2)O(2)-generating system, we selected a ROS-resistant MCF-7
breast cancer cell line, namely Resox cells. By exploring different survival pathways that are usually induced during oxidative stress, we identified a constitutive overexpression of the endoplasmic reticulum chaperone,
GRP94, in these cells, whereas levels of its cytoplasmic homolog HSP90, or
GRP78, were not modified. This overexpression was not mediated by constitutive unfolded protein response (UPR) activation. The increase in
GRP94 is tightly linked to an increase in cell proliferation and migration capacities, as shown by GRP94-silencing experiments. Interestingly, we also observed that
GRP94 silencing inhibits migration and proliferation of the highly aggressive MDA-MB-231 cells. By immunohistochemistry, we showed that
GRP94 expression was higher in recurrent human breast
cancers than in their paired primary
neoplasias. Similar to the situation in the Resox cells, this increase was not associated with an increase in UPR activation in recurrent
tumors. In conclusion, this study suggests that
GRP94 overexpression may be a hallmark of aggressiveness and recurrence in breast
cancers.